Osteoarthritis (OA) is a progressive degenerative disorder characterized by a breakdown of the cartilage in the joints, a deterioration of the synovial fluid present in the articular joints, and a subchondral osteosclerosis accompanied by osteophyte formation. Patients with OA often exhibit severe pain that affects many aspects of their daily living. The prevalence of OA increases with age, with more than 60% of those 60 years old or older likely to have some cartilage abnormality (Bjelle (1982) Scand. J. Rheumatol. Suppl., 43:35-48). OA has become the most costly form of arthritis, collectively accounting for up to 1-2.5% of the gross national product of Western nations (Reginster (2002) Rheumatology, 41 (Suppl. 1):3-6).
Synovial fluid lubricates and protects the intra-articular joint surfaces. The fluid is primarily composed of high molecular weight polysaccharide hyaluronan (HA, sodium salt of hyaluronic acid, also known as sodium hyaluronate). The concentration of HA in the normal human synovial joint fluid is approximately 3 mg/ml. HA consists of repeating disaccharide units of N-acetylglucosamine and sodium glucuronate (FIG. 1). HA in the normal synovial fluid of the joints contains 12,500 disaccharide units with total molecular weight (MW) of 5 MDa (Balazs et al. (1993) J. Rheumatol. Suppl., 39:3-9). In OA patients, the concentration and MW of HA in synovial fluid decreases, resulting in the diminished capacity of the fluid to protect the cartilage.
Intra-articular injection of an elastoviscous solution containing high molecular weight HA has been shown to restore the normal homeostasis of the diseased joint. This procedure, known as viscosupplementation, has proven effective in reducing pain and enhancing joint function (see, e.g., Balazs et al. (1993) J. Rheumatol. Suppl., 39:3-9; Wobig (1998) Clin. Ther., 20(3):410-423).
A number of HA-based viscosupplements are available on the market and new products are being developed. Viscosupplements vary in a number of characteristics including, for example, the source of HA (animal-derived or bacterial), the concentration and MW of HA, and the type and degree of chemical crosslinking used, if any. Usually, most viscosupplements contain 5-15 mg/ml HA and, once injected, have residence half-life between hours to several days. Such viscosupplements are injected into the knee in 2-3 ml unit volumes in a series of three to five injections each one week apart. In some cases, pain relief occurs within a few days, continues to progress over a few weeks, and often lasts for several months, even up to a year. For example, knee viscosupplementation with Synvisc® (hylan G-F 20; Genzyme Corp., Cambridge, Mass.) administered three times at 2 ml weekly has been demonstrated to be at least as good, or better, than continuous oral therapy with non-steroidal anti-inflammatory drugs (NSAIDs) plus arthrocentesis over a period of 6 months (Adams et al. (1995) Osteoarthritis and Cartilage, 3:213-225) and more effective than a saline placebo or arthrocentesis controls (Moreland (1993) Am. Coll. Rheumatol. (57th Ann. Sci. Meeting, Nov. 7-11, San Antonio, Tex.), 165; Wobig (1998) Clin. Ther., 20(3):410-423).
The series of multiple injections have been thought to be essential for a prolonged (six months to one year) effect on osteoarthritic pain primarily because of the short residence half-life of most viscosupplements (Peyron (1993) J. Rheumatol., 20(Suppl. 39):10-15). For example, an intra-articular residence half-life of 1% HA with an average MW of 1.7-2.6 MDa is 11 hours, as determined in rabbits. As MW of HA increases, so does the residence half-life (e.g., 1% hylan A, in which the average MW of HA is 6 MDa, has a half-life of 1.2±1 day). However, even an insoluble gel, such as hylan B containing 0.4% HA, has a relatively short residence half-life of 7.7±1 days. Consistent with the half-life data, three 2 ml injections of Synvisc® (hylan G-F 20) into an OA knee were demonstrated to be significantly more effective for reducing OA pain than two 2 ml injections (Scale et al. (1994) Curr. Ther. Res., 55(3):220-232).
For treatment with Synvisc® of patients with OA of the hip, the recommended dose is one 2 ml injection with a second optional injection administered between one and three months if insufficient pain relief is experienced (Chevalier (2000) Am. Coll. Rheumatol. (64th Annual Scientific Meeting, Oct. 30-Nov. 3, Philadelphia, Pa.)). In hip OA patients, a single intra-articular injection of Synvisc® (hylan G-F 20) at 2 ml showed a significant immediate and sustained symptomatic effect in the majority of enrolled patients for up to three months (duration of the study). It has not been investigated whether greater volumes of viscosupplements, such as Synvisc® (hylan G-F 20) (e.g., 4, 6 ml or greater), could offer equivalent or better efficacy with fewer injections compared to multiple injection of 2-3 ml, or a single injection of 2 ml. As far as was known, the use of larger volumes potentially posed a risk of local adverse effects such as pain, swelling, and effusion.
Durolane™ (Q-Med AB, Uppsala, Sweden) is the only viscosupplement that is recommended to be injected once, at 3 ml. It is an epoxy-crosslinked viscosupplement with a longer reported half-life (4 weeks) and a higher concentration of HA (20 mg/ml). The prolonged residence time is thought to allow the reduced number of injections. Nevertheless, a single injection of Durolane™ did not demonstrate statistical benefits over placebo (Altman et al. (2004) Osteoarthritis and Cart., 12:642-649).
Thus, prior to the present invention, it was not known whether a single injection of an HA-based viscosupplement, particularly one with a short residence life, can produce a desired long-term therapeutic effect.
The use of fewer injections offers apparent advantages over the multiple injections, including avoidance of adverse effects, reduced costs, and better patient compliance. A continued need exists to develop new viscosupplementation treatments that provide effective relief to OA patients without necessitating multiple injections.